Ancient drug curcumin impedes 26S proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2

Sourav Banerjee, Chenggong Ji, Joshua E. Mayfield, Apollina Goel, Junyu Xiao, Jack E. Dixon, and Xing Guo
PNAS August 7, 2018 115 (32) 8155-8160; published ahead of print July 9, 2018 https://doi.org/10.1073/pnas.1806797115

  1. Contributed by Jack E. Dixon, June 18, 2018 (sent for review April 20, 2018; reviewed by Tony Hunter and Carol MacKintosh)

Significance

Curcumin is an ancient drug derived from turmeric and has been found to exhibit potent anticancer properties albeit through controversial mechanisms of action. Using a biochemical model, mouse cancer model, and cellular models, we show that curcumin is a highly potent and selective inhibitor of dual-specificity tyrosine-regulated kinase 2 (DYRK2), a positive regulator of the 26S proteasome. Curcumin perturbs 26S proteasome activity via DYRK2 inhibition in various cancer cells and in the mouse cancer model leading to impairment of cell proliferation and reduction of cancer burden in mice. This novel mechanism of action of curcumin opens up new avenues for potential preventative or therapeutic strategies in proteasome-addicted cancers like triple-negative breast cancer and multiple myeloma.

Abstract

Curcumin, the active ingredient in Curcuma longa, has been in medicinal use since ancient times. However, the therapeutic targets and signaling cascades modulated by curcumin have been enigmatic despite extensive research. Here we identify dual-specificity tyrosine-regulated kinase 2 (DYRK2), a positive regulator of the 26S proteasome, as a direct target of curcumin. Curcumin occupies the ATP-binding pocket of DYRK2 in the cocrystal structure, and it potently and specifically inhibits DYRK2 over 139 other kinases tested in vitro. As a result, curcumin diminishes DYRK2-mediated 26S proteasome phosphorylation in cells, leading to reduced proteasome activity and impaired cell proliferation. Interestingly, curcumin synergizes with the therapeutic proteasome inhibitor carfilzomib to induce apoptosis in a variety of proteasome-addicted cancer cells, while this drug combination exhibits modest to no cytotoxicity to noncancerous cells. In a breast cancer xenograft model, curcumin treatment significantly reduces tumor burden in immunocompromised mice, showing a similar antitumor effect as CRISPR/Cas9-mediated DYRK2 depletion. These results reveal an unexpected role of curcumin in DYRK2-proteasome inhibition and provide a proof-of-concept that pharmacological manipulation of proteasome regulators may offer new opportunities for anticancer treatment.

Footnotes

  • ↵1S.B. and C.J. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: jedixon{at}ucsd.edu or xguo{at}zju.edu.cn.

  • Author contributions: S.B., J.X., J.E.D., and X.G. designed research; S.B., C.J., and J.E.M. performed research; A.G. contributed new reagents/analytic tools; S.B., C.J., J.E.M., J.X., and J.E.D. analyzed data; and S.B., J.E.D., and X.G. wrote the paper.

  • Reviewers: T.H., The Salk Institute for Biological Studies; and C.M., University of Dundee.

  • The authors declare no conflict of interest.

  • Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.wwpdb.org (PDB ID code 5ZTN).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1806797115/-/DCSupplemental.

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Ancient drug curcumin impedes 26S proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2
Sourav Banerjee, Chenggong Ji, Joshua E. Mayfield, Apollina Goel, Junyu Xiao, Jack E. Dixon, Xing Guo
Proceedings of the National Academy of Sciences Aug 2018, 115 (32) 8155-8160; DOI: 10.1073/pnas.1806797115
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